miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice

Abstract

Skeletal muscle mass and homeostasis during postnatal muscle development and regeneration largely depend on adult muscle stem cells (satellite cells). We recently showed that global overexpression of miR-378 significantly reduced skeletal muscle mass in mice. In the current study, we used miR-378 transgenic (Tg) mice to assess the in vivo functional effects of miR-378 on skeletal muscle growth and regeneration. Cross-sectional analysis of skeletal muscle tissues showed that the number and size of myofibers were significantly lower in miR-378 Tg mice than in wild-type mice. Attenuated cardiotoxin-induced muscle regeneration in miR-378 Tg mice was found to be associated with delayed satellite cell activation and differentiation. Mechanistically, miR-378 was found to directly target Igf1r in muscle cells both in vitro and in vivo. These miR-378 Tg mice may provide a model for investigating the physiological and pathological roles of skeletal muscle in muscle-associated diseases in humans, particularly in sarcopenia.

Lack of miR-378 attenuates muscular dystrophy in mdx mice

“…So far, the literature data regarding the function of miR-378 in mSCs are rather inconclusive. Although in vitro studies performed on C2C12 myoblasts demonstrated that miR-378 accelerates differentiation by targeting either musculin, the myogenic differentiation inhibitor (20), or bone morphogenetic protein 4 (BMP4) (59), in vivo experiments on primary mSCs revealed that Tg mice overexpressing miR-378 exhibit delayed muscle regeneration upon acute, cardiotoxin-induced muscle injury by direct targeting insulin-like growth factor 1 receptor (Igf1r) (24). In the current study, the KO of miR-378 in dystrophic animals did not alter the number of mSCs but resulted in a diminished contribution of activated mSCs within the total mSCs, together with decreased proliferation status of mSCs.…”

“…Simultaneously, it was demonstrated as one of the most upregulated miRNAs in the serum of different mouse models of the disease, as well as in DMD patients, emphasizing its potential utility as a circulating biomarker (22,23). Even more, Zeng et al demonstrated that overexpression of miR-378 attenuated muscle regeneration by delaying mSC activation and differentiation upon cardiotoxin-induced muscle injury (24). Therefore, we sought to explore the role of miR-378 loss in a murine model of DMD, mdx mice, with the special emphasis on pathobiology and severity of the hallmark symptoms of the disease.…”

Altered miRNA and mRNA Expression in Sika Deer Skeletal Muscle with Age

“…It has been reported that the overexpression of miR-378 significantly reduced the skeletal muscle mass in mice. Mir-378 attenuated muscle regeneration by delaying the activation and differentiation of satellite cells in mice, especially in sarcopenia [62]. However, there were relatively few studies on target genes for miR-378 to regulate myopenia.…”

Using computer simulation models to investigate the most promising microRNAs to improve muscle regeneration during ageing

“…The gene for miR-378 is in the first intron of Pgc-1β and so is expressed more in metabolically active tissue and it has been shown to activate the pyruvate-PEP futile cycle in skeletal muscle of mice whereby it enhances lipolysis in adipose tissue and ameliorates obesity 44 . A further study by the same group showed that miR-378 targets Igfr1 in mice leading to defective muscle regeneration 45 .…”